Our previous studies demonstrated a correlation between the tumor-inducing capacities and the susceptibilities to destruction in vitro by host natural killer (NK) cells and activated macrophages (AM) among hamster cell lines transformed by adenoviruses (Ad) 2 and 12 and SV40. The results of studies using somatic cell hybrids formed between cytolytic susceptible, weakly oncogenic Ad2-transformed cells and cytolytic resistant, highly oncogenic SV40-transformed cells indicated that the expression of the early, Ad2-encoded gene products in hybrid cells was associated with an increase in cytolytic susceptibility and a reduction in tumor-inducing capacity. This examination of the correlation between virus gene expression, cytolytic susceptibility, and tumor-inducing capacity has been expanded to include 19 hybrid cell lines derived from each of three different Ad2-transformed parental cell lines and one SV40-transformed parental cell line. In all cases in which the Ad2 early gene products are expressed in these hybrid cells, an increased cytolytic susceptibility and decreased tumor-inducing capacity has been observed; conversely, all hybrid cells that do not express Ad2 early gene products have been found to be relatively resistant to cytolysis and as tumorigenic as the nonhybrid SV40 parental cell line. These results suggest that the increased cytolytic susceptibility associated with the expression of Ad2 early gene products in these hybrids may be causally linked to the reduction in tumor-inducing capacity of these cell lines. To explore the extent of the cytolytic resistant transformed cell phenotype among papovavirus-transformed hamster cells, cell lines were derived following in vitro transformation with polyoma, BK virus, and bovine papilloma virus. Cell lines transformed by these three papovaviruses were found to be as resistant to NK cell and AM destruction and as tumorigenic as were SV40-transformed hamster cells. Therefore, a state of cytolytic resistance appears to be a general property of papovavirus-transformed hamster cells. Hamster cell lines transformed by SV40 early genome deletion mutants with variable-sized deletions between SV40 map positions 0.54 and 0.59 that induce qualitatively altered or undetectable amounts of SV40 specific small-t protein were found to express the same cytolytic resistant phenotype and the same tumorigenic phenotype as cell lines transformed by wild-type virus, indicating that SV40 small-t protein plays no role in these two transformed cell phenotypes. (IB)